Open AccessJournal Article
In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-derived Growth Factor Receptors Determination of a Pharmacokinetic/Pharmacodynamic Relationship
Dirk B. Mendel,A. Douglas Laird,Xiaohua Xin,Sharianne G. Louie,James G. Christensen,Guangmin Li,Randall E. Schreck,Tinya Abrams,Theresa J. Ngai,Leslie Lee,Lesley J. Murray,Jeremy P. Carver,Emily Chan,Katherine G. Moss,Joshua Ö. Haznedar,Juthamas Sukbuntherng,Robert A. Blake,Li Sun,Cho Tang,Todd W. Miller,Sheri Shirazian,Gerald Mcmahon,Julie M. Cherrington +22 more
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TLDR
The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.Abstract:
One challenging aspect in the clinical development of molecularly targeted therapies, which represent a new and promising approach to treating cancers, has been the identification of a biologically active dose rather than a maximum tolerated dose. The goal of the present study was to identify a pharmacokinetic/pharmacodynamic relationship in preclinical models that could be used to help guide selection of a clinical dose. SU11248, a novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well as antiangiogenic activity via targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), KIT, and FLT3 receptor tyrosine kinases, was used as the pharmacological agent in these studies. In mouse xenograft models, SU11248 exhibited broad and potent antitumor activity causing regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. To predict the target SU11248 exposure required to achieve antitumor activity in mouse xenograft models, we directly measured target phosphorylation in tumor xenografts before and after SU11248 treatment and correlated this with plasma inhibitor levels. In target modulation studies in vivo , SU11248 selectively inhibited Flk-1/KDR (VEGF receptor 2) and PDGF receptor β phosphorylation (in a time- and dose-dependent manner) when plasma concentrations of inhibitor reached or exceeded 50–100 ng/ml. Similar results were obtained in a functional assay of VEGF-induced vascular permeability in vivo . Constant inhibition of VEGFR2 and PDGF receptor β phosphorylation was not required for efficacy; at highly efficacious doses, inhibition was sustained for 12 h of a 24-h dosing interval. The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.read more
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References
More filters
Journal ArticleDOI
The hallmarks of cancer.
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
Journal ArticleDOI
Cell signaling by receptor-tyrosine kinases
TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
Journal ArticleDOI
Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo.
TL;DR: It is shown that expression of an endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), is induced in astrocytoma cells but is dramatically upregulated in two apparently different subsets of glioblastoma cells, which strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify VEGF as a potential tumourAngiogenesis factor in vivo.
Journal ArticleDOI
Signaling by Receptor Tyrosine Kinases
TL;DR: The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane gly-coprotein tyrosine receptor kinases (RTK) and stimulates intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival.
Journal ArticleDOI
Molecular and biological properties of vascular endothelial growth factor.
TL;DR: Current evidence indicates that VEGF is essential for embryonic vasculogenesis and angiogenesis, and both therapeuticAngiogenesis using recombinant V EGF or VEGFs gene transfer and inhibition of VEGf-mediated pathological angiogenic are being pursued.
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